1. Technical Field
This disclosure related to the treatment of Alzheimer's disease (AD), the most common human neurodegenerative disease of the CNS resulting in progressive neuronal death and memory loss. More specifically, an antisense oligonucleotide against neutral sphingomyelinase and GW4869, a chemical inhibitor of neutral sphingomyelinase, are shown to inhibit activation of glial cells and protect neurons in AD cell culture and animal models. As a result, new treatment options for AD patients are disclosed.
2. Description of the Related Art
Alzheimer's disease (AD) is a neurodegenerative disorder resulting in progressive neuronal death and memory loss. Neuropathologically, the disease is characterized by neurofibrillary tangles and neuritic plaques. Neurofibrillary tangles are composed of the hyperphosphorylated tau protein. On the other hand, neuritic plaques are mainly composed of aggregates of amyloid-β (Aβ) protein, a 40-43 amino acid proteolytic fragment derived from the amyloid precursor protein (APP) that is over-expressed in AD (Martin, 1999). Histopathologically, this disease is characterized by infiltration of inflammatory cells into the CNS, gliosis, and neuronal apoptosis.
Although deposition of Aβ peptides is one of the primary causes of neuronal loss in AD, mechanisms by which Aβ causes neuronal loss are largely unknown. Several lines of evidence suggest that neurons are killed through neurotoxic molecules elaborated from glial activation. Consequently, activated astrocytes and microglia are characteristically found in abundance near amyloid plaques in AD and in mouse models of AD, and amyloid peptides have been reported as glial activators in the presence of an immunological co-factor. Activated glia are also found to increase substantially in the hippocampus and neocortex of the aging brain. Consistently, microinjection of pre-aggregated Aβ1-42 peptides into the nucleus basalis of the rat produces a congophylic deposit followed by microglial and astrocyte activation and a strong inflammatory reaction surrounding the dystrophic neuritis.
Therefore, controlling glial activation and hence inflammation are of great therapeutic interest in mitigating neuronal cell death in different neurological disorders including AD. Because ceramide, the lipid second messenger molecule, produced from the degradation of sphingomyelin by sphingomyelinases (neutral and acidic) induces apoptosis and cell death in various cell types, including glial and neuronal cells. It was decided to investigate the N-SMase-ceramide pathway in Aβ-activated glia-mediated neuronal death. Here, the evidence that (A+IL-i)-activated astrocytes induce the activation of sphingomyelinases and the production of ceramide in human primary neurons is presented. The activation of neutral, but not acidic, sphingomyelinase plays a key role in neuronal apoptosis in response to neurotoxins released from activated astrocytes is shown. Further, blocking of astroglial activation by N-SMase inhibition prevented the release of neurotoxic substances. Subsequently, inhibition of astroglial N-SMase suppressed NF-κB activation in activated astroglia. The in vitro data were further substantiated by in vivo findings where it has been found that antisense oligonucleotides against N-SMase prevented astrogliosis and microgliosis and protected neurons in the cortex of Aβ-injected C57/BL6 mice.